This invention relates to 2,3,4,5-tetrahydro-1H-3-benzazepines having anti-psychotic activity, and also to the synthesis of .alpha.-substituted-arylacetamides, especially fused-ring nitrogen heterocycles, in particular dihydroindoles, 1,2,3,4-tetrahydroisoquinolines and 1,2,3,4,5,6-hexahydro-3-benzazocines, and most particularly 2,3,4,5-tetrahydro-1H-3-benzazepines.
Dihydroindoles, 1,2,3,4-tetrahydroisoquinolines, 1,2,3,4,5,6-hexahydro-3-benzazocines, and particularly 2,3,4,5-tetrahydro-1H-3-benzazepines are known to have useful pharmacological properties. For example, U.S. Pat. Nos. 3,393,192, 3,609,138, 4,011,319, 4,284,555 and 4,477,378, and British Patent Specification no. 1,118,688, all describe 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines having various activities described as antibacterial effects, central nervous system effects and hypotensive effects.
Weinstock et al. in Drugs of the Future, Vol. 10, No. 8, pp. 645-697 (1985) discuss the profound effect that 1-phenyl substituents have on the dopaminergic activity of certain types of benzazepines; see in particular Table II on page 666.
European Patent Application No. 83105610.6 (published as 0 096 838) discloses certain 1-aryloxy-2,3,4,5-tetrahydro-1H-3-benzazepines optionally having alkoxy substituents in the 7- and/or 8-position; these compounds are disclosed as having utility in treating depression.
U.S. Pat. No. 5,015,639 describes and claims 2,3,4,5-tetrahydro-1H-3-benzazepines lacking a 1-phenyl group but having instead a variety of 1-substituents including a group of the formula ##STR1## wherein m is 0 or 1, and each of the groups R.sup.9, which can be the same or different, is a hydrogen atom or an alkyl, alkoxy, alkoxyalkyl, aralkyl or aryl group. These compounds have good anti-dopaminergic activity, and in particular show surprising selectivity for the D-1 subclassification of dopaminergic receptors. Iorio et al., Pharmacol. Exp. Ther. (1983), 226, page 462, and Iorio et al. in Neurobiology of Central D.sub.1 -Dopamine Receptors, pages 1-14 in Advances in Experimental Medicine and Biology 204, Eds. Creese and Breese, Plenum, New York, 1986, have also evaluated the effects of benzazepines on dopamine receptors. Charifson et al., J. Med. Chem. (1988), 31, pages 1941-1946, have similarly evaluated 1,2,3,4-tetrahydroisoquinolines.
International Application No. PCT/US 91/04046 describes and claims (inter alia) compounds having the structural formula A ##STR2## and the pharmaceutically acceptable salts thereof, wherein: R.sup.10 represents H, C.sub.1-4 -alkyl, allyl or cyclopropylmethyl;
R.sup.11 represents C.sub.3-8 -cycloalkyl or C.sub.5-8 -cycloalkenyl; PA1 R.sup.12 represents C.sub.1-4 -alkyl; and PA1 R.sup.13 represents (inter alia) R.sup.12, H or R.sup.12 CO. PA1 wherein R.sup.4 is selected from aromatic groups, 1-alkenyl groups and 1-cycloalkenyl groups; PA1 and X is a leaving group, e.g., --OSO.sub.2 F or an activated ester group. PA1 R.sup.4 is a 1-cycloalkenyl group; PA1 R is an alkyl, alkenyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl group; PA1 and Y is an oxygen atom or H.sub.2 ; PA1 and their non-toxic salts with bases when R.sup.1 is or contains a hydroxy group; PA1 and their non-toxic acid addition salts when Y is H.sub.2.
These compounds are useful in the treatment of psychoses, depression, pain and hypertension.
Ciufolini et al., Tetrahedron Letters 1987, Vol. 28 No. 2, 171-174, have described a `model` intramolecular arylation of 2-[2-(2-iodophenyl)ethyl]-indane-1,3-dione with tetrakis(triphenyphosphine)palladium(0), to yield a spiro(indane-1,3-dione-2,1'-indane), in experiments on the synthesis of Friedricamycin. In further studies of prototype substrates and also of substrates used in studies of the synthesis of Friedricamycin, Ciufolini et al., J. Org. Chem. [Communications] 1988, 53, 4149-4151, have described intramolecular arylations of `soft` enolates (i.e., enolates having a pK.sub.a &lt;15) catalyzed by zerovalent palladium. A phenyl halide moiety in one part of the molecule was condensed with an enol in another part of the molecule to provide a benzo-fused five- or sixmembered homocyclic or heterocyclic ring; but compounds with a fused four-membered ring could not be produced. One example in Table I therein shows the formation of an indolone by intramolecular condensation of an N-methyl-N-(2-ethoxycarbonylpropanoyl)-2-iodoanilide. In an adaptation of this method, Piers et al., J. Org. Chem. 1990, 55, 3454-3455, have disclosed a five-membered ring annulation method based on Pd(0)-catalyzed intramolecular coupling of a vinyl iodide function with an enolate anion function; in this method, the enolate anion was in a saturated five- or six-membered ring.
A modification of the reaction disclosed by Ciufolini et al. was published by Negishi et al., J. Am. Chem. Soc., 1989, 111, 8018-8020. Using compounds analogous to those which, in the hands of Ciufolini et al., had failed to produce compounds with a fused four-membered ring, there were able to effect a cyclization in the presence of carbon monoxide under pressure: the product was a ketone with its carbonyl group (provided by the carbon monoxide) in a fused five-membered ring. They were similarly able to produce analogous ketones with the carbonyl group in a fused six- or seven-membered ring, and even effect the cyclization on non-cyclic intermediates to produce unfused cyclopentenones.
In all these reactions catalyzed by a zerovalent metal, the enolate is generally stabilized by an adjacent activating group (such as estercarbonyl, keto-carbonyl or nitrite).